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Key Data Regarding The Risk

FDA's decision to require a Risk Evaluation and Mitigation Strategy (REMS) and class-labeling changes to the drug labels for Long-Acting Beta Agonists (LABAs) is based on analyses from the Salmeterol Multicenter Asthma Research Trial (SMART), the Salmeterol Nationwide Surveillance study (SNS), and a meta-analysis conducted by FDA in 2008 and discussed at the joint Pulmonary Allergy Drugs, Drug Safety and Risk Management, and Pediatric Advisory Committees, held on December 10-11, 2008 (for complete safety reviews and background information discussed at this meeting see the following link: December 10-11 2008 AC meeting).

SMART was a large, randomized, 28-week, placebo-controlled trial that evaluated a total of 26,355 patients 12 years of age and older receiving standard asthma therapy and the addition of either salmeterol or placebo. Results showed that patients receiving salmeterol were at an increased risk for asthma-related death compared to patients receiving placebo (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). Subgroup analyses were also performed and found that asthma-related death in Caucasians and African Americans occurred at a higher rate in patients using salmeterol compared to placebo. The SNS was a 16-week, double-blind study that compared the addition of salmeterol or albuterol to standard asthma therapy in 25,180 asthma patients who were 12 years of age and older. In this study, there was an increase in the number of respiratory and asthma-related deaths in the salmeterol group compared to the albuterol group (0.07% [12 out of 16,787 patients]) compared to the albuterol group (0.02% [2 out of 8393 patients] relative risk of 3.0, p=0.105]).

Table I. SMART Results

In preparation for the December 2008 Advisory Committee, FDA conducted a meta-analysis of 110 studies evaluating the use of LABAs in 60,954 patients with asthma. The meta-analysis used a composite endpoint to measure severe exacerbation of asthma symptoms (asthma-related death, intubation, and hospitalization). The results of the meta-analysis suggested an increased risk for severe exacerbation of asthma symptoms in patients using LABAs compared to those not using LABAs. The largest risk difference per 1000 treated patients was seen in children 4-11 years of age, see table 2 below. The results of the meta-analysis were primarily driven by asthma-related hospitalizations. Other meta-analyses evaluating the safety of LABAs in the treatment of asthma have not shown a significant increase in the risk for severe asthma exacerbations.

Table 2. Meta-Analysis Results: Number of Patients Experiencing an Event*

At this time, there are insufficient data to conclude whether using LABAs with an inhaled corticosteroid reduces or eliminates the risk of asthma-related death and hospitalizations. FDA is requiring the manufacturers of LABAs to conduct studies evaluating the safety of LABAs when used in conjunction with an inhaled corticosteroid.

Based on the available information, FDA concludes there is an increased risk for severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and adult patients as well as death in some patients using LABAs for the treatment of asthma. The agency is requiring the REMS and class-labeling changes to improve the safe use of these products.

See February 2010 LABA Drug Safety Communication for more information.

References

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Please see full Prescribing Information and Medication Guide, including Boxed Warning.

Indication

PERFOROMIST (formoterol fumarate) Inhalation Solution is used for the long-term treatment of chronic obstructive pulmonary disease (COPD) including chronic inflammation of the lungs (bronchitis) and emphysema. It is only to be used with a nebulizer and is taken twice daily (morning and evening).

WARNING: ASTHMA-RELATED DEATH

PERFOROMIST Inhalation Solution belongs to a class of drugs called long-acting beta2-agonists (LABA). People with asthma who take LABA such as PERFOROMIST Inhalation Solution have an increased risk of death from asthma problems. Do not use PERFOROMIST Inhalation Solution if you have asthma without using a long-term asthma control medicine.

IMPORTANT SAFETY INFORMATION

Warnings and Precautions
PERFOROMIST Inhalation Solution should not be used instead of rescue inhaler or nebulized medicine for the treatment of acute symptoms. Extra doses of PERFOROMIST Inhalation Solution should not be used for that purpose since overuse can cause serious heart problems, including death. Acute or sudden symptoms should be treated with an inhaled short-acting beta2-agonist. Seek immediate medical attention if:

  • your symptoms quickly worsen despite recommended doses of PERFOROMIST Inhalation Solution
  • PERFOROMIST Inhalation Solution treatment becomes less effective
  • you need more inhalations of a short-acting beta2-agonist (rescue inhaler or nebulized medicine) than usual.

Do not use PERFOROMIST Inhalation Solution with other LABA medicines for any reason.

How to Use PERFOROMIST Inhalation Solution
Use PERFOROMIST Inhalation Solution exactly as directed by your health care professional. Do not stop using PERFOROMIST Inhalation Solution or other medicines to control or treat your COPD unless told to do so by your health care professional because your symptoms might get worse. Your health care professional will change your medicines as needed.

Co-existing Conditions
The use of PERFOROMIST Inhalation Solution with certain health conditions or with certain medications can cause serious side effects. Tell your health care professional about all of your health conditions, including if you:

  • have heart problems
  • have high blood pressure
  • have diabetes
  • have seizures
  • have thyroid problems
  • have liver problems
  • are pregnant or planning to become pregnant. It is not known if PERFOROMIST Inhalation Solution can harm an unborn baby.
  • are breastfeeding. It is not known if PERFOROMIST Inhalation Solution passes into breast milk and if it can harm your baby.

Drug Interactions
Tell your health care professional about all the medicines you take including prescription and over-the-counter medicines, vitamins and herbal supplements. PERFOROMIST Inhalation Solution and certain other medicines may interact with each other and cause serious side effects.

Side Effects
The most common side effects reported in patients taking PERFOROMIST Inhalation Solution were diarrhea, nausea, nasopharyngitis, dry mouth, dizziness, and insomnia. Serious side effects may include sudden shortness of breath, serious allergic reactions, chest pain, increased or decreased blood pressure, a fast and irregular heartbeat, low blood potassium, high blood sugar, and high blood acid.

You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.